Combinatorial organic synthesis is becoming an important tool in drug discovery. Methods for the synthesis of large numbers of diverse compounds have been described [Ellman, et. al. Chem. Rev. 96: 555–600 (1996)], as have methods for tagging systems [Ohlmeyer et al., Proc. Natl. Acad. Sci. USA, 90, 10922–10926, (1993)]. The growing importance of combinatorial synthesis has created a need for molecules which can be readily elaborated into libraries by simple and readily variable chemistry. Because the literature abounds with methods for fashioning amide bonds and with methods for protecting nonreacting groups from the chemical transformations induced by reagents for fashioning amide bonds, molecules that offer differentiable amines are of great utility as so-called scaffolds for combinatorial synthesis.
Receptors are molecules which selectively interact with other molecules. Antibodies, which represent one class of naturally occurring receptor molecules, bind to other molecules (antigens) with very high selectivity; they are also known to catalyze chemical reactions by selectively binding the transition states. Monoclonal antibodies are used as medicinal and diagnostic agents. Although antibodies are proteins, all receptor molecules need not be proteins. Receptor molecules perform a variety of tasks from selective binding of substrates to catalyzing chemical reactions, and their effectiveness is dependent upon their ability to bind molecular species (substrates or acceptors) with high selectivity. For example, the free energy for an antibody binding its antigen is normally from 6–15 kcal/mol.
There is considerable interest in synthetic receptors and libraries thereof. For example, Still et al. (U.S. Pat. No. 5,804,563 and PCT US95/00572) have described synthetic receptors which comprise a polyfunctional organic template covalently linked to two or more oligomers. In Still's case, as well as in the present invention, the oligomers may be oligoamides, oligoesters, oligoureas, oligourethanes, oligoamines, oligoethers, oligosulfonamides, oligonucleotides, oligosaccharides, peptides, etc.
In the construction of a library, a template or scaffold (the two will be used interchangeably herein) may be linked to a solid substrate and to an identifier which uniquely defines the synthetic receptor. The identifier is a stable chemical molecule or a plurality of stable chemical molecules distinguishable and detectable to picomolar levels. Usually the template is covalently linked to a solid support which is in turn covalently linked to the identifier, but in some embodiments the template may be directly attached to the identifier. (See PCT application WO 95/19567.)
Throughout this application, various references are referred to within parentheses or square brackets. The disclosures of these publications in their entireties are hereby incorporated by reference into this application. Variables are defined when introduced and retain that definition throughout. The term “combinatorial library” refers to a collection of molecules based on logical design and involving the selective combination of building blocks by means of simultaneous chemical reactions. Each species of molecule in the library is referred to as a member of the library.